Search Results (54)

Recently, a number of new genes (NFE2L2, HFE, HMOX, HIF-1α, ALOX5, GPX4, PTGS2, and IL-6) have been recognized as playing a role in ferroptosis and genetic predisposition to cardiovascular diseases (CVDs). Identifying these novel genes may facilitate the discovery of therapeutic agents and improve the clinical evaluation of phenotypes and prognoses in CVD patients. In the future, it will be crucial to develop genetic markers that correlate with clinical outcomes for individuals with CVDs. This review highlights recent developments in ferroptosis research while interpreting how genetic factors may contribute to the pathogenesis of CVDs. Understanding this relationship could be invaluable for predicting disease progression in individual patients, informing suitable medical interventions, and facilitating early diagnosis and treatment. Furthermore, we examine the possible uses of these disorders in diagnosis and the various treatment strategies, along with the associated challenges and existing limitations. Full article

Cardiac iron overload is a rare but important adverse consequence of systemic iron overload, marked by the abnormal accumulation of iron in the myocardium. It is most typically caused by hereditary hemochromatosis (mutations in the HFE gene) or secondary iron overload conditions, such as transfusion-dependent anemias. Excess iron in the myocardium causes oxidative stress, cardiomyocyte damage, and progressive fibrosis, ultimately leading to cardiomyopathy. Clinical manifestations are diverse and may include heart failure, arrhythmias, and restrictive or dilated cardiomyopathy. Given the worsened prognosis with cardiac involvement, timely diagnosis and management are essential to improve clinical outcomes. This review provides a contemporary overview of the cardiovascular complications associated with iron overload, including clinical manifestations, diagnostic approaches, and treatment options. Full article

Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence. Full article

Parkinson’s Disease (PD) is the most frequent movement disorder and is second only to Alzheimer’s Disease as the most frequent neurodegenerative pathology. Early onset Parkinson’s disease (EOPD) is less common and may be characterized by genetic predisposition. NGS testing might be useful in the diagnostic assessment of these patients. A panel of eight genes (SNCA, PRKN, PINK1, DJ1, LRRK2, FBXO7, GBA1 and HFE) was validated and used as a diagnostic tool. A total of 38 in sequence EOPD patients of the Parkinson’s Disease Unit of our Hospital Institution were tested. In addition, the number of the hexanucleotide repeats of the C9ORF72 gene and the frequency of main HFE mutations were evaluated. Six patients were carriers of likely pathogenic mutations in heterozygosity in the analyzed genes, one of them presented mutations in association and another had a complex genetic background. Their clinical symptoms were correlated with their genotypes. In the cohort of patients, only the p.Cys282Tyr of HFE was significantly decreased in the dominant model and allele contrast comparison. Only one patient with one allele of C9ORF72 containing 10 repeats was identified and clinically described. The clinical signs of sporadic and monogenic PD are often very similar; for this reason, it is fundamental to correlate genotypes and phenotypes, as we tried to describe here, to better classify PD patients with the aim to deepen our knowledge in the molecular mechanisms involved and collaborate in reaching a personalized management and treatment. Full article

Background/Objectives: Chronic venous insufficiency (CVI), a chronic vascular dysfunction, is a common health problem that causes serious complications such as painful varicose veins and even skin ulcers. Identifying the underlying genetic and epigenetic factors is important for improving the quality of life of individuals with CVI. In the literature, many genes, variants, and miRNAs associated with CVI have been identified through genomic and transcriptomic studies. Despite molecular pathogenesis studies, how the genes associated with CVI are regulated by miRNAs and the effect of variants in binding regions on expression levels are still not fully understood. In this study, previously identified genes, variants, and miRNAs associated with CVI, common variants in the mRNA-miRNA binding regions, were investigated using in silico analyses. Methods: For this purpose, miRNA research tools, MBS (miRNA binding site) database, genome browsers, and the eQTL Calculator in the GTEx portal were used. Results: We identified SNVs associated with CVI that may play a direct role in the miRNA-mediated regulation of the ZNF664, COL1A2, HFE, MDN, MTHFR, SRPX, TDRD5, TSPYL4, VEGFA, and APOE genes. In addition, when the common SNVs in the mRNA binding region of 75 unique CVI related-miRNAs in five candidate genes associated with CVI were examined, seven miRNAs associated with the expression profiles of ABCA1, PIEZO1, and CASZ1 genes were identified. Conclusions: In conclusion, the relationship between genetic markers identified in the literature that play a role in the pathogenesis of the CVI and the expression profiles was evaluated for the first time in the mRNA-miRNA interaction axis. Full article

Hereditary hemochromatosis (HH) related to HFE-gene mutations is a well-known condition, yet its understanding remains complex. The BIOIRON classification emphasizes that only homozygosity for the C282Y mutation should be considered pathogenic. The penetrance of HFE-related HH is highly variable. Symptoms are often challenging to recognize at the time of presentation, and the systemic involvement may overlap with other diseases. Hyperferritinemia and elevated transferrin saturation levels are still the milestones in HH diagnosis, but they are also common findings in many other clinical conditions. Furthermore, current diagnostic and therapeutic guidelines are not always unequivocal in defining HH patients’ characteristics, as well as treatment management and goals. Our work provides a concise overview of the latest evidence regarding pathogenic mechanisms, clinical picture, differential diagnosis and diagnostic tools. Alongside this, it summarizes and compares the main recommendations from principal guidelines issued by the 2017 Hemochromatosis International Meeting, the American College of Gastroenterology, the European Association for the Study of the Liver, the European Molecular Genetics Quality Network, the DUTCH guidelines, and the British Society for Haematology. Summarizing tables for quick consultation are also provided. Full article

Background/Objectives: Increased interest in personalized nutrition has led to a growing focus on exploring genetic variants and their impact on nutritional uptake (nutrigenomics). Nevertheless, no systematic review to date has compiled scientific evidence on genetic variants (such as single-nucleotide polymorphisms (SNPs)) affecting mineral metabolism in humans. This review aims to fill this gap and enable optimized personalized nutrition recommendations in health care. Methods: Cochrane, Embase and MEDLINE databases were systematically searched for English and German studies published between 2007 and 2023, focusing on genetic variants linked to nutrition. Studies on overweight, diseased, or underage individuals were excluded. Papers with verified findings were assessed for methodological quality using the Joanna Briggs Institute critical appraisal tool. Results: Twenty-one scientific papers on SNPs associated with mineral metabolism were included. The majority were observational studies (n = 19) conducted on Caucasian populations. Women outnumbered men (37.4%) women, 18.9% men, 43.7% sex not reported. All identified SNPs linked to minerals influenced iron parameters, with the TMPRSS6 gene showing the strongest correlation. Two HFE SNPs (rs1800562 and rs1799945) and one TF SNP (rs1799852) exhibited protective effects, while the other 11 SNPs were linked to increased risk of iron deficiency, suggesting potential benefits from iron supplementation for individuals with those genetic variants. Conclusions: This review provides comprehensive insights into the association between genetic variants and mineral metabolism, and the findings highlight the relevance of genetic makeup in optimizing health through nutritional interventions. The generalizability of the findings may be limited to Caucasians, warranting future research with diverse populations. This review was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) on 12 July 2022, under INPLASY202270068 and funded by the University Centre for Prevention and Sports Medicine at Balgrist University Hospital Zurich and the Swiss Innovation Agency Innosuisse, Switzerland. Full article

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan–Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini–Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01–4.08], p = 0.034 and Adj HR: 1.53 [1.09–2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48–0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06–2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37–0.73], and Adj HR: 0.51 [CI: 0.36–0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Full article

Background: Hereditary hemochromatosis (HH) is a genetic condition with fatigue as an essential but not precisely assessed symptom. While some well-specified scales for fatigue assessment in some pathologies exist, data on their usefulness in HH need to be collected. This research aimed to evaluate fatigue in HH using the Fatigue Assessment Scale (FAS), Fatigue Severity Scale (FSS), and Chalder Fatigue Scale (CFQ). Methodology: Seventy-nine HH patients underwent a questionnaire containing items about detailed medical history and the FAS, FSS, and CFQ scales. Twenty-five sex- and age-matched healthy persons constituted the control group (controls); additionally, thirty blood donors (donors) were compared. Results: The fatigue indices were significantly worse in the HH patients than in the controls and donors (HH vs. controls p-value: FAS = 0.003, FSS < 0.001, and CFQ = 0.003; HH vs. donors p-value: FAS = 0.025, FSS < 0.001, and CFQ = 0.041). There were no differences between the severity of fatigue and the specific genotype or the age of the patients. The HH women presented more severe fatigue than the men. High internal consistency and reliability for each scale were revealed: the Cronbach alpha values were as follows: FAS 0.92, FSS 0.95, and CFQ 0.93. Additionally, the construct validity and factorial validity of the implemented scales were confirmed. Conclusions: The HH patients exhibited significantly worse fatigue across all the scales. The FAS, FSS, and CFQ are simple and reliable diagnostic tools for assessing and quantifying fatigue for clinical and research purposes. Full article

Iron is a vital element involved in a plethora of metabolic activities. Mammalian systemic iron homeostasis is mainly modulated by hepcidin, the synthesis of which is regulated by a number of proteins, including the hemochromatosis-associated proteins Hfe and Transferrin Receptor 2 (TfR2). Macrophages play versatile functions in iron homeostasis by storing iron derived from the catabolism of erythrocytes and supplying iron required for erythropoiesis. The absence of Hfe in macrophages causes a mild iron deficiency in aged mice and leads to an overproduction of the iron exporter Ferroportin 1 (Fpn1). Conversely, TfR2 gene silencing in macrophages does not influence systemic iron metabolism but decreases transcription of the macrophage Fpn1 in adult mice and modulates their immune response. This study investigated cellular and systemic iron metabolism in adult and aged male mice with macrophage-specific Hfe and TfR2 silencing (double knock-out, DKO). Serum iron parameters were significantly modified in aged animals, and significant differences were found in hepatic hepcidin transcription at both ages. Interestingly, splenic iron content was low in adult DKOs and splenic Fpn1 transcription was significantly increased in DKO animals at both ages, while the protein amount does not reflect the transcriptional trend. Additionally, DKO macrophages were isolated from mice bone marrow (BMDMs) and showed significant variations in the transcription of iron genes and protein amounts in targeted mice compared to controls. Specifically, Tranferrin Receptor 1 (TfR1) increased in DKO adult mice BMDMs, while the opposite is observed in the cells of aged DKO mice. Fpn1 transcript was significantly decreased in the BMDMs of adult DKO mice, while the protein was reduced at both ages. Lastly, a significant increase in Erythropoietin production was evidenced in aged DKO mice. Overall, our study reveals that Hfe and TfR2 in macrophages regulate hepatic Hepc production and affect iron homeostasis in the spleen and BMDMs, leading to an iron deficiency in aged animals that impairs their erythropoiesis. Full article

The Human Genome Project, completed in 2003, heralded a new era in precision medicine. Somewhat tempering the excitement of the elucidation of the human genome is the emerging recognition that there are fewer single gene disorders than first anticipated, with most diseases predicted to be polygenic or at least gene-environment modified. Hereditary haemochromatosis (HH) is an inherited iron overload disorder, for which the vast majority of affected individuals (>90%) have homozygosity for a single pathogenic variant in the HFE gene, resulting in p.Cys282Tyr. Further, there is significant benefit to an individual in identifying the genetic risk of HH, since the condition evolves over decades, and the opportunity to intervene and prevent disease is both simple and highly effective through regular venesection. Add to that the immediate benefit to society of an increased pool of ready blood donors (blood obtained from HH venesections can generally be used for donation), and the case for population screening to identify those genetically at risk for HH becomes more cogent. Concerns about genetic discrimination, creating a cohort of “worried well”, antipathy to acting on medical advice to undertake preventive venesection or simply not understanding the genetic risk of the condition adequately have all been allayed by a number of investigations. So why then has HH population genetic screening not been routinely implemented anywhere in the world? The answer is complex, but in this article we explore the pros and cons of screening for HH and the different views regarding whether it should be phenotypic (screening for iron overload by serum ferritin and/or transferrin saturation) or genotypic (testing for HFE p.Cys282Tyr). We argue that now is the time to give this poster child for population genetic screening the due consideration required to benefit the millions of individuals at risk of HFE-related iron overload. Full article

Hemochromatosis (HC) is the main genetic disorder of iron overload and is regarded as metal-related human toxicosis. HC may result from HFE and rare non-HFE gene mutations, causing hepcidin deficiency or, sporadically, hepcidin resistance. This review focuses on HFE-related HC. The illness presents a strong biochemical penetrance, but its prevalence is low. Unfortunately, the majority of patients with HC remain undiagnosed at their disease-curable stage. The main aim of HC management is to prevent iron overload in its early phase and remove excess iron from the body by phlebotomy in its late stage. Raising global awareness of HC among health staff, teaching them how not to overlook early HC manifestations, and paying attention to careful patient monitoring remain critical management strategies for preventing treatment delays, upgrading its efficacy, and improving patient prognosis. Full article

Alzheimer’s disease (AD), a multifactorial neurodegenerative disorder, is prevalent among the elderly population. It is a complex trait with mutations in multiple genes. Although the US Food and Drug Administration (FDA) has approved a few drugs for AD treatment, a definitive cure remains elusive. Research efforts persist in seeking improved treatment options for AD. Here, a hybrid pipeline is proposed to apply text mining to identify comorbid diseases for AD and an omics approach to identify the common genes between AD and five comorbid diseases—dementia, type 2 diabetes, hypertension, Parkinson’s disease, and Down syndrome. We further identified the pathways and drugs for common genes. The rationale behind this approach is rooted in the fact that elderly individuals often receive multiple medications for various comorbid diseases, and an insight into the genes that are common to comorbid diseases may enhance treatment strategies. We identified seven common genes—PSEN1, PSEN2, MAPT, APP, APOE, NOTCH, and HFE—for AD and five comorbid diseases. We investigated the drugs interacting with these common genes using LINCS gene–drug perturbation. Our analysis unveiled several promising candidates, including MG-132 and Masitinib, which exhibit potential efficacy for both AD and its comorbid diseases. The pipeline can be extended to other diseases. Full article

Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients. Sequencing alignment, variant calling, and annotation were performed using standard methods. Polymerase chain reaction (PCR) coupled with Sanger sequencing and immunoblot analysis were used to validate specific gene variants. cBioPortal and Gene Set Enrichment Analysis (GSEA) were used for actionable target analysis. We identified 148,881 gene variants, representing 57,121 and 50,150 variants in the female and male cohorts, respectively, of which 251 were highly significant and MASH sex-specific (p < 0.0286). Polymorphisms in CAPN14, SLC37A3, BAZ1A, SRP54, MYH11, ABCC1, and RNFT1 were highly expressed in male liver samples. In female samples, Polymorphisms in RGSL1, SLC17A2, HFE, NLRC5, ACTN4, SBF1, and ALPK2 were identified. A heterozygous variant 1151G>T located on 18q21.32 for ALPK2 (rs3809983) was validated by Sanger sequencing and expressed only in female samples. Immunoblot analysis confirmed that the protein level of β-catenin in female samples was 2-fold higher than normal, whereas ALPK2 expression was 0.5-fold lower than normal. No changes in the protein levels of either ALPK2 or β-catenin were observed in male samples. Our study suggests that the perturbation of canonical Wnt/β-catenin signaling observed in postmenopausal women with MASH could be the result of polymorphisms in ALPK2. Full article

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE²⁺ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment. Full article